Vascular disorders include atherosclerosis, Sickle cell, Scleroderma and associated organ complications. Sickle cell disease (SCD) is one of the most common monogenic disorders where more than 250,000 children affected with SCD are born each year worldwide. See Roberts I, De montalembert M, Sickle cell disease as a paradigm of immigration hematology: new challenges for hematologists in Europe, Haematologica, 2007; 92(7):865-71. See Weatherall D J, Clegg J B., Inherited haemoglobin disorders: an increasing global health problem, Bull World Health Organ, 2001; 79(8):704-12.
SCD has the widest distribution throughout sub-Saharan Africa, India and the Middle East. See Weatherall D J, Clegg J B., Inherited haemoglobin disorders: an increasing global health problem, Bull World Health Organ, 2001; 79(8):704-12.
It is estimated that the prevalence of the SCD trait in Saudi Arabia is 4.2%. In the US it affects about 72,000 people, and 2 million people are carriers, most of whom are African Americans. See Alhamdan N A, Almazrou Y Y, Alswaidi F M, Choudhry A J, Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. Genet Med., 2007; 9(6):372-7. See Creary M, Williamson D, Kulkarni R., Sickle cell disease: current activities, public health implications, and future directions, J Womens Health (Larchmt), 2007; 16(5):575-82.
Owing to advances in health care, better nutrition, and infection control, there has been a reduction in children's mortality and consequently an increased prevalence of SCD and hemoglobin disorders. See Weatherall D J, Clegg J B., Inherited haemoglobin disorders: an increasing global health problem, Bull World Health Organ, 2001; 79(8):704-12.
The SCD burden on patients is manifested by the acute and chronic complications of the disease such as painful crises, acute chest syndrome, stroke, and multi-organ failure. Additionally, vasoocclusive crisis with high pain rates is a major risk factor for early death. See Platt O S, Brambilla D J, Rosse W F, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J. Med., 1994; 330(23):1639-44.
Other risks include aplastic crises, splenic sequestration, and cerebrovascular accidents. A recent study showed that 48% of SCD patients had documented, irreversible organ damage by the fifth decade, including pulmonary hypertension, stroke and end stage renal disease. See Powars D R, Chan L S, Hiti A, Ramicone E, Johnson C., Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients, Medicine (Baltimore), 2005; 84(6):363-76.
Nowadays, current treatment strategies for SCD involve the use of chronic blood transfusion, hydroxyurea, and bone marrow transplantation. These treatments might have strong evidence for their role in the disease management, but obviously are not without significant side effects. Patients who are receiving chronic blood transfusions are at high risk of infection, immunologic reactions and iron overload. Additionally, it might be not feasible for children and their families to keep in good compliance on this treatment, since it requires a long term commitment and includes many hazardous side effects. Leukemia has been reported after long-term treatment with hydroxyurea, in addition to neutropenia and thrombocytopenia. Bone marrow transplantation is the only curative treatment for SCD, but not the optimal practical strategy. It needs a well-matched donor and carries the risk of graft rejection and neurologic complications.
With respect to Hemoglobin Polymerization, the primary event in SCD molecular pathogenesis is polymerization of deoxygenated hemoglobin S (HbS). See Bunn H F., Pathogenesis and treatment of sickle cell disease, N Engl J. Med., 1997; 337(11):762-9.
Owing to the presence of valine in the β-globin chain, deoxygenated HbS will make a hydrophobic interaction via valine with complementary sites on a neighboring hemoglobin molecule, triggering an aggregation of hemoglobin molecules into large polymers. This mechanism distorts the shape of the red blood cells (RBCs) and decreases its deformability, leading to the formation of rigid sickle cells. These cells will lead to vasoocclusive crisis development, one of the major complications of SCD. See Bunn H F., Pathogenesis and treatment of sickle cell disease, N Engl J. Med., 1997; 337(11):762-9. See Gabriel A, Przybylski J., Sickle-cell anemia: A Look at Global Haplotype Distribution, Nature Education, 2010; 3(3):2-12.
With respect to Abnormal Adhesion to Vascular Endothelium, sickle red blood cells interact abnormally with the vascular endothelium, and this is thought to be one of the primary initiating factors in the development of micro-vascular occlusions in SCD. See Hebbel R P, Yamada O, Moldow C F, Jacob H S, White J G, Eaton J W., Abnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease, J Clin Invest., 1980; 65(1):154-60.
Sickle erythrocytes stay persistently bound to the endothelium despite an increase in shear force inside the vessels, which is opposite to the behavior of normal RBCs. There are probably multiple interaction mechanisms contributing to the adhesion, either directly or through bridging protein.
Two pathways may explain the consequences of sickle RBCs' abnormal interaction. First, the sickle, rigid cells are trapped inside the vessels, which leads to polymerization of HbS and obstructs the arteries. See Bunn H F., Pathogenesis and treatment of sickle cell disease, N Engl J. Med., 1997; 337(11):762-9. Second, sickle cells' adhesion increases the activity of the nuclear factor κB and endothelin-1, and upregulates vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) adhesion molecules' activity, (see Mosseri M, Bartlett-pandite A N, Wenc K, Isner J M, Weinstein R., Inhibition of endothelium-dependent vasorelaxation by sickle erythrocytes, Am Heart J., 1993; 126(2):338-46) (see Phelan M, Perrine S P, Brauer M, Faller D V, Sickle erythrocytes, after sickling, regulate the expression of the endothelin-1 gene and protein in human endothelial cells in culture, J Clin Invest., 1995; 96(2):1145-51) which result in vessel wall injury, remodeling, and occlusion.
With respect to Inflammation, Vascular disorders include atherosclerosis, Sickle cell, Scleroderma and associated organ complications. There is evidence that inflammation plays a major role in the development of the vasoocclusive complications associated with SCD. This collectively triggers the production of cytokines, leading to upregulation of proinflammatory cells and activation of the inflammatory responses and ultimately to further vascular injury. Additionally, NO function in reducing the inflammatory mediators may contribute to the development of cerebrovascular disease in sickle cell anemia, because nitric oxide is low in these patients. It has been suggested that hydroxyurea might have a role in SCD treatment by decreasing the neutrophil count, but this area needs further research.
With respect to Hemolysis, Reperfusion Injury and Nitric Oxide, it is well known that hemolysis plays an integral part in sickle cell anemia. Its role is due to the accumulation of cell-free hemoglobin, leading to NO conversion to the inactive metabolites nitrate and methemoglobin, (see Olson J S, Foley E W, Rogge C, Tsai A L, Doyle M P, Lemon D D., No scavenging and the hypertensive effect of hemoglobin-based blood substitutes, Free Radic Biol Med., 2004; 36(6):685-97) making it ineffective in controlling vessel tone. Hemolysis also is leading to depletion of NO by overwhelming the removal system.
Recurrent episodes of vasoocclusion and reperfusion play a major role in the pathogenesis of vascular injury in sickle cell anemia. Studies showed that reperfusion injury is due to transcription factors activation, leucocytes adhesion, and production of free radicals in the endothelium. See Kaul D K, Hebbel R P., Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice, J Clin Invest., 2000; 106(3):411-20.
Consequently, release of toxic free radicals due to oxidative stress (see Mcbride A G, Borutaite V, Brown G C., Superoxide dismutase and hydrogen peroxide cause rapid nitric oxide breakdown, peroxynitrite production and subsequent cell death, Biochim Biophys Acta., 1999; 1454(3):275-88) leads to decreased availability of nitric oxide in the blood stream. All of this leads to vasoconstriction and platelet aggregation, and contributes to vascular dysfunction in SCD.
With respect to Hyper-coagulation, activation of the coagulation system is significant in SCD pathogenesis. Studies showed that patients with SCD are more likely to have ischemic stroke and pulmonary embolism due to thrombosis development. These patients' high level of D-dimer, antithrombin III, plasmin: antiplasmin complex, and low levels of proteins C and S in the bloodstream make the role of coagulation factors obvious. See Francis R B., Elevated fibrin D-dimer fragment in sickle cell anemia: evidence for activation of coagulation during the steady state as well as in painful crisis, Haemostasis, 1989; 19(2):105-11. See Tomer A, Harker L A, Kasey S, Eckman J R., Thrombogenesis in sickle cell disease, J Lab Clin Med., 2001; 137(6):398-407.
Additionally, in sickle cell patients there is evidence of platelet activation and monocytes' abnormal expression of tissue factor. See Shet A S, Aras O, Gupta K, et al., Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes, Blood, 2003; 102(7):2678-83.
Exposure of phosphatidylserine of sickle cell's membrane is another factor that might contribute to the hyper-coaguable state by activation of prothrombin.